title: Influence of dopamine on GABA release in striatum: evidence for D1-D2 interactions and non-synaptic influences.
abstract: Striatal slices from the rat were preincubated with [3H]GABA and superfused in the presence of nipecotic acid and aminooxyacetic acid, inhibitors of high-affinity GABA transport and GABA aminotransferase, respectively. GABA efflux was estimated by monitoring tritium efflux, 98% of which was in the form of [3H]GABA. The following three major observations were made: (1) The overflow of GABA evoked by electrical field stimulation (8 Hz) was increased two-fold by SKF-38393 (10 microM), an agonist at the D1 family of dopamine receptors. This increase was completely blocked by the D1 receptor antagonist SCH-23390 (10 microM). However, SCH-23390 had no effect on GABA overflow when given alone. Thus, dopamine agonists appear to exert an excitatory influence on GABA release; however, this effect was not elicited by endogenous dopamine under the conditions of this experiment. (2) Electrically evoked GABA overflow was reduced 50% by quinpirole (10 microM), an agonist at the D2 family of dopamine receptors, and this effect was blocked by the D2 antagonist sulpiride (10 microM). Moreover, exposure to sulpiride alone caused a 60% increase in GABA overflow, and this effect was abolished by 3-iodotyrosine (2 mM), a dopamine synthesis inhibitor. Thus, D2 agonists appear to exert an inhibitory influence on dopamine release, an effect that can be exerted by endogenous stores of dopamine. (3) The stimulatory effect of SKF-38393 was attenuated by quinpirole, whereas the sulpiride-induced increase in GABA efflux was attenuated by SCH-23390. Sulpiride also increased [3H]GABA efflux during KCl-induced depolarization, an effect that was antagonized by SCH-23390 as in the case of electrical stimulation. However, although tetrodotoxin did not alter the stimulatory effect of sulpiride, it did block the ability of SCH-23390 to antagonize the sulpiride-induced increase in GABA overflow. These latter results suggest that there is an interaction between D1 and D2 receptors whereby the effects of dopamine mediated via D1 sites are inhibited by an action on D2 sites. In conclusion, our results suggest that (i) dopamine agonists can exert an excitatory influence on depolarization-induced GABA release within neostriatum via D1 receptors and an inhibitory influence via D2 receptors; (ii) under the conditions of these experiments, endogenous dopamine fails to act on D1 sites but does exert an inhibitory influence via D2 sites; and (iii) there is an interaction between D1 and D2 receptors such that the actions of dopamine mediated via D1 sites are inhibited as a result of the concomitant actions exerted via D2 sites.
authors.affiliation: Department of Neuroscience, University of Pittsburgh, PA 15260, USA.
authors.forename: L G
authors.initials: LG
authors.lastname: Harsing
authors.forename: M J
authors.initials: MJ
authors.lastname: Zigmond
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000502:physiology; D004298:Dopamine / Q000502:physiology*; D065127:Dopamine D2 Receptor Antagonists; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008297:Male; D007470:Monoiodotyrosine / Q000494:pharmacology; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010477:Perfusion; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000502:physiology
chemical_list: D065127:Dopamine D2 Receptor Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D007470:Monoiodotyrosine; D011188:Potassium; D002118:Calcium; D004298:Dopamine